Effect of plasmapheresis for acute humoral rejection after heart transplantation

OBJECTIVE: The objective of this study was to report our experience of treating acute humoral rejection with plasmapheresis in heart transplant (HT) recipients. PATIENTS AND METHODS: From May 1996 to December 2005, 238 HTs were performed using therapy with cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisolone as well as induction treatment with rabbit anti-human thymocyte globulin. Endomyocardial biopsy for rejection surveillance was performed weekly for the first month, monthly for 3 months, yearly after the first year, and whenever rejection was suspected. Immunofluorescence studies with IgG, IgM, C3, C4, C1q, and HLA-DR were performed routinely on the first month biopsy. After a 2-year trial, immunofluorescence studies were not performed routinely, because no significant findings were observed; thus they were performed only when clinical deterioration, unstable hemodynamic status, or suspicion of rejection occurred on routine echocardiographic examinations. Plasmapheresis with fresh frozen plasma exchanging twice the blood volume of the patients was performed for 5 days. Rescue immunosuppression with methylprednisolone (1 g/d) was delivered for 3 days and the immunosuppressants changed, but no intravenous immunoglobulin was prescribed. RESULTS: Twelve patients suffered biopsy-proven acute humoral rejection at 3 days to 32 months after HT (mean, 9.4 months). Immunofluorescence studies showed positive HLA-DR in 7 patients; IgG in 4 patients; IgM in 1 patient; C3 in 4 patients; C4 in 1 patient; and C1q in 1 patient. One patient who was 3 months after HT showed only C1q positive but was treated with extracorporeal membrane oxygenation and intra-aortic balloon pumping support and died 1-month after plasmapheresis. Another patient who deteriorated on the 3rd postoperative day and died 3 days after plasmapheresis was considered to have vascular rejection by interstitial edema, vacuolated endothelial cells and no pathognomonic clinical features, although there was no positive immunofluorescence result. All other subjects were discharged from the hospital, although 3 required mechanical support during plasmapheresis. Hypotension with hypocalcemia was frequently noted during plasmapheresis. The 1-year survival rate was 75% +/- 11%, and 5-year survival rate, 51% +/- 15%. CONCLUSION: Plasmapheresis with concurrent rescue immunosuppression was an effective treatment for acute humoral rejection in HT even with unstable hemodynamics.     

A case of Mycobacterium chelonae mediastinitis and acute humoral rejection after heart transplantation

Mediastinitis is one of the life‐threating complications that can occur after cardiac surgery. However, to the best of our knowledge, there has been no report of mediastinitis caused by Mycobacterium chelonae, which is one of the rapidly growing nontuberculous mycobacteria species. As far as we know, our case is the first case describing the curative management for mediastinitis caused by M. chelonae after heart transplantation.     

Diagnosis and treatment of acute humoral rejection after kidney transplantation: preliminary experience

BACKGROUND: Acute humoral rejection, or rejection associated with de novo production of anti-HLA donor-specific antibodies (DSA) after kidney transplantation (KTx), is a clinicopathologic entity that is not completely understood. Recent studies have proposed criteria for its diagnosis, including: (1) steroid-resistant acute dysfunction; (2) positive post-Tx donor-specific crossmatch (XM); and (3) widespread C4d deposits in peritubular capillaries (PTC) upon renal biopsy. METHODS: During 2002, prospective screening for AHR was established at our unit, seeking DSA post-KTx in selected cases of steroid-resistant acute rejection or acute dysfunction in high-risk sensitized or re-Tx patients. Frozen donor lymphocytes were used for post-Tx flow cytometry (FC) XM and high-definition flow PRA for patients with no frozen donor cells. We treated patients diagnosed with DSA using plasma exchange and polyclonal immunoglobulin. RESULTS: Post-Tx DSA studies were performed in 9 of 94 patients transplanted during 2002. We detected DSA post-Tx in 3 of 9 recipients: 2 by FCXM and 1 using high-definition flow PRA. Two were highly sensitized pre-Tx, but the third patient was a 70-year-old woman receiving a first Tx (PRA=0%). All 3 recipients presented with severe steroid-resistant acute renal dysfunction during the first 2 weeks post-Tx. Biopsies showed some features of AHR (neutrophils in PTC); 1 case showed no signs of concomitant cellular rejection. All rejection episodes were treated successfully (XM became negative and renal function recovered) by combining plasma exchange and polyclonal immunoglobulin. CONCLUSIONS: The use of specific tools, like the crossmatch, in cases of acute, steroid-resistant renal graft dysfunction is important to identify and treat otherwise undetected humoral mechanisms of rejection.     

肾移植术后急性体液性排斥反应的监测及其临床意义

目的 探讨肾移植后发生急性体液性排斥反应(AHR)的可能机制,及其在临床早期诊断和防治AHR中的重要意义.方法 回顾分析2006年1月至2010年12月间296例肾移植受者的临床资料.肾移植术后,采用酶联免疫吸附试验(ELISA)动态监测受者群体反应性抗体(PRA)和供者特异性抗体(DSA)水平,采用免疫组织化学法和HE染色检查移植肾组织的病理形态学改变及C4d的沉积、浸润淋巴细胞表面分子标记.AHR诊断标准参照Banff 2005标准,并结合受者的临床相关指标.结果 296例受者中,术后共有25例发生了AHR,发生率为8.4％ (25/296).术前PRA阳性者和阴性者术后AHR的发生率分别为23.1％(6/26)和7.0％(19/270),两者比较,差异有统计学意义(P＜0.01).术后发生AHR和未发生AHR受者的DSA阳性率分别为88.0％(22/25)和0.4％(1/271),出现C4d沉积阳性率分别为80.0％(20/25)和6.7％ (4/60),两者间DSA阳性率和C4d沉积阳性率的比较,差异均有统计学意义(P＜0.01).通过调整免疫抑制方案和(或)应用静脉注射免疫球蛋白、血浆置换、抗胸腺细胞球蛋白及利妥昔单抗等治疗后,19例AHR被逆转,其余6例因治疗无效,发生移植肾破裂,导致移植肾被切除.结论 PRA和DSA在肾移植术后AHR的发生中起重要作用,术后应立即开始监测PRA和DSA,以达到预防、早期诊断和合理治疗AHR的目的,进而改善移植肾的存活.     

Rituximab therapy for acute humoral rejection after kidney transplantation

A pilot study was performed on eight consecutive renal-transplant (RT) patients presenting with acute humoral rejection (AHR) to assess the efficacy of monoclonal anti-B cell antibodies, such as rituximab (375 mg/m weekly) for 3 to 5 consecutive weeks, in addition to plasma exchange (PE), steroids, mycophenolate mofetil, and tacrolimus. AHR was associated with increased serum creatinine, the appearance of donor-specific alloantibodies (DSA), and the presence of C4d in a transplant biopsy. After a follow-up of 10 months (range 7-23), patient and graft survivals were 100% and 75%, respectively. Renal function improved in six cases in which serum creatinine decreased from 297+/-140 to 156+/-53 micromol/L (P=0.015); graft loss occurred in two cases; and four patients had infectious complications. At last follow-up, DSA had disappeared or decreased in four cases. Rituximab therapy, in addition to PE, might be of benefit for RT patients presenting with AHR.     

The correlation between humoral antibodies and rejection after renal transplantation

Sera from 36 renal transplant patients were selected at random and screened for cytotoxic antibodies to a panel of 50 normal lymphocytes and 3 lymphoblasts. 11 of these patients had received more than one kidney transplant. None of the primary renal transplants demonstrated cytotoxic antibodies to the panel of normal cells. However, 4 of the retransplant patients were found to possess cytoxins. These 4 sera were cytotoxic to the normal cell panel (10%, 20%, 50% and 70% of panel lysed) as well as to certain lymphoblasts. 30% of the sera negative to the normal cell panel demonstrated cytoxins to the lymphoblasts; 15% positive to only the B-lymphoblasts, 5% positive to only the T-lymphoblasts and 10% showed cytotoxic antibodies to both T and B-lymphoblasts and 10% showed cytotoxic antibodies to both T and B-lymphoblasts. No correlation between cytotoxicity and inhibition of MLR was obvious. Of the 14 sera showing cytotoxicity to lymphoblasts, 9 exhibited MLR inhibition. However, inhibition of MLR was not found to be restricted to B-cell cytotoxic sera. These sera were tested by radioimmunoassay. A good correlation was found between acute rejection and percent increase in direct binding of patients sera to radiolabelled B-lymphoblast membranes. Of the 36 sera tested the six sera obtained from patients in acute rejection bound the iodinated lysate to a significantly greater amount than the controls. As yet, no characterization of the antigen specificities has been found.     

Treatment of humoral rejection in kidney transplantation

Acute antibody-mediated rejection (acute humoral rejection [AHR]) of organ allografts presents most of the time as severe dysfunction with a high risk of allograft loss. Peritubular capillary complement C4d deposition is diagnostic of AHR in kidney allografts and is associated with circulating donor-specific anti-HLA alloantibodies. Removal of alloantibodies with suppression of antibody production and rejection reversal is now possible. Therapeutic strategies that include combinations of plasmapheresis (or immunoadsorption), mycophenolate mofetil, tacrolimus, and/or intravenous immunoglobulins have been used to successfully treat AHR. The optimal protocol to treat humoral rejection remains to be defined. Anti-CD20 monoclonal antibody therapy (rituximab) aiming at depleting B cells and suppressing antibody production has been used as a rescue therapy in some episodes of refractory humoral rejection. Plasmapheresis and/or intravenous polyclonal immunoglobulin, as well as rituximab, have also been used to successfully “desensitize” selected high-immunologic risk patients who were in anticipation of crossmatch-positive (or ABO-incompatible) kidney transplantation. Recent data suggest that chronic kidney allograft rejection might also be monitored by complement C4d in biopsies. The efficacy and safety of immunosuppressive drugs such as tacrolimus, mycophenolate mofetil (or enteric-coated mycophenolic acid), sirolimus, or everolimus in controlling antidonor humoral responses in patients with chronic allograft dysfunction remains to be studied prospectively. The combination of tacrolimus and mycophenolate mofetil appears to effectively suppress antidonor antibody production. In the near future, the possible role of specific anti–B-cell approaches with drugs, such as rituximab, or possibly of new anti–T-cell activation approaches using selective agents such as belatacept should be assessed to refine the management of chronic allograft dysfunction.     

血浆置换联合利妥昔单抗治疗肾移植术后抗体介导的排斥反应1例报告并文献复习

目的探讨血浆置换联合利妥昔单抗治疗肾移植术后抗体介导排斥反应(antibodymediated rejection,AMR)的疗效。方法回顾分析1例发生AMR的肾移植受者的临床资料并复习相关文献。结果 1例女性患者,肾移植术后7年,分娩后移植肾失功,1年后行二次肾移植术。术后予他克莫司(FK506)+麦考酚吗乙酯(MMF)+泼尼松三联免疫抑制治疗,肾功能正常。术后5 d患者出现突发尿少,移植肾区胀痛,群体反应性抗体(PRA)Ⅰ类分子升高至14.29%,供体特异性抗体(donor-specific antibody,DSA)阳性,血清肌酐(Scr)升高达606μmol/L,予血浆置换1次(血浆2 000 ml),置换后给予单剂利妥昔单抗500 mg静脉滴注,治疗18 d后复查PRA及DSA阴性,尿量增加,肾功能恢复正常。患者随访至2011年6月,查PRA及DSA一直维持阴性,肾功能良好。结论血浆置换联合利妥昔单抗用于治疗肾移植术后AMR有一定疗效。     

The role of splenectomy in the setting of refractory humoral rejection after kidney transplantation

Living donor kidney transplantation remains the best option for presensitized recipients to avoid excessive time on the waiting list. However, the possibility for a positive crossmatch with a potential living donor is high. A desensitization protocol may be required to avoid antibody-mediated rejection (AMR). Current protocols are not always effective to prevent AMR and in some cases fail to convert subjects to a negative crossmatch before transplantation. From March 2006 to January 2011, the 11 presensitized patients who displayed AMR after living donor kidney transplantation underwent splenectomy as a rescue procedure due to failure of standard rejection treatments. Splenectomy was considered to be effective in six recipients who normalized their renal function without the need for other immunomodulating therapy. Our analysis suggested that splenectomy can be successfully performed alone or in association with other treatments like bortezomib or rituximab to overcome severe AMR.     

Bortezomib is effective to treat acute humoral rejection after liver transplantation

Introduction

Acute humoral rejection (AHR), a rare complication in orthotopic liver transplantation (OLT), responds poorly to conventional therapies. Bortezomib, a proteasome inhibitor, has been shown to be effective in treating plasma cell-derived tumors and acute rejection episodes after renal transplantation. Herein, we have reported our clinical experience with bortezomib as a novel approach to treat AHR after OLT.

Methods

We retrospectively analyzed the 247 adult OLTs performed from January 2007 to April 2011. Patients with AHR who were treated with steroid pulses, rituximab (375 mg/m²), and plasmapheresis (PP) were assigned to group A. Group B subjects were prescribed steroid pulses, rituximab, PP, and bortezomib (1.3 mg/m²), after March 2009.

Results

Among the 9 patients (3.6%) diagnosed with AHR, all subjects in group A (n = 3) died within several days after AHR, whereas 4/6 (66.7%) group B patients were rescued and 3 (50%) survived at a mean follow-up 22.3 months (range, 18-26).

Conclusion

Proteasome inhibitor-based therapies provide a more effective strategy to treat AHR after OLT.     

C-reactive protein in the monitoring of acute rejection after heart transplantation

Histological examination of endomyocardial biopsy (EMB) is the main technique for rejection surveillance after heart transplantation. This technique is elaborate, inconvenient for the patient, and not without complications. We prospectively analyzed whether the measurement of C-reactive protein (CRP), an acute phase protein that quickly rises when there is inflammation, can serve as a marker for immunological quiescence and as an indicator for withholding EMB. During a 6-month period, CRP was measured in all patients referred for EMB as part of the routine follow-up after heart transplantation. Acute rejection in patients with a follow-up of more than 1 year was rare (1/76). In the majority of cases, EMB was taken within the 1-year post-transplantation (170/246 = 69 %). In 71/170 biopsies (42 %), CRP was ≤ 1; in the other 99/170 (58 %), CRP was ≥ 2. When CRP was ≤ 1, acute rejection was diagnosed in 12/70 cases (17 %). In contrast, acute rejection was found in 28/99 cases (28 %) with CRP ≥ 2 (P = 0.1). Although CRP is elevated more often in the presence of acute rejection, its sensitivity does not allow CRP to replace the routine performance of EMB for monitoring rejection after heart transplantation. We did, however, find a prognostic significance with regard to the effect of rejection treatment: in all acute rejections with a CRP ≤ 3 (n = 11), steroids were effective. Received: 6 January 1998 Received after revision: 7 April 1998 Accepted: 20 April 1998     

Specific humoral rejection of a pancreas allograft in a recipient of pancreas after kidney transplantation.

A 46 year-old male patient who had received a pancreas transplant,subsequent to a kidney transplant (PAK) for diabetes nephropathy,was admitted to our transplant unit for an acute hyperglycaemiaassociated with a mild increase of creatinine. His type 1 diabetes was declared around his 5th birthday andwas complicated by a proliferative retinopathy, nephropathy,arteritis and ischaemic cardiomyopathy. After a 4-year period of haemodialysis, a renal transplantationwas performed in August 1996 from a deceased donor sharing onlyone human leukocyte antigen (HLA) DR Ag (Table 1). After a shortperiod of delayed graft function, renal function improved andstabilized at a creatinine level of around 140 µmol/l.Initial immunosuppression included induction treatment withanti-T lymphocyte globulins (Thymoglobulin, Genzyme, USA) anda maintenance regimen associating tacrolimus and     

Relationship between CMV and graft rejection after heart transplantation

Abstract  This study, which included 153 heart transplant patients, was designed to determine whether the cytomegalovirus (CMV) status of both donor and recipient may influence graft rejection. The follow-up was 1 year and they all received the same triple-drug immunosup-pressive regimen with induction (antilymphocyte serum). There was no difference in the total rejection rate, but an increase in repeated rejection rate was shown in transplant recipients with hearts from CMV seropositive donors ( P < 0.05). These data strongly suggest the impact of CMV in enhancement but not in induction of rejection. To prevent iterative rejection in the CMV seropositive donor group, antiviral therapy could be proposed during enhancement of antirejection therapy.